PROJECT SUMMARY The adverse consequences of HIV and related comorbidities on the central nervous system remain prevalent despite highly effective antiretroviral therapy, with approximately 40% of persons living with HIV showing neurocognitive impairment (NCI). Compared to other ethnic/racial groups in the United States, HIV infected (HIV+) Hispanics/Latinos/as, hereafter referred to as Hispanics, present with increased risk for NCI and neurocognitive decline; and this risk is particularly pronounced in older age. Yet, the factors underlying these disparities are not well understood. Guided by the National Institute of Minority Health and Health Disparities Research Framework, the present proposal aims to identify key mechanisms underlying adverse neurocognitive outcomes among Hispanics aging with HIV. Among the potential predictors of NCI in this group, the proposed study will focus on two biological processes -- metabolic syndrome and gut microbiome dysbiosis -- that may be particularly problematic among Hispanics and may result in greater brain vulnerability to HIV. The study will also integrate aspects of the physical/built and sociocultural environment (assessed via geocoding) that have been linked to metabolic syndrome and NCI, and investigate their influence on neurocognitive disparities in HIV. We will also explore the impact of behavioral (physical activity and diet) and healthcare (healthcare use and access, health literacy) variables. We will collect these data in 200 HIV+ and HIV-uninfected Hispanics (approximately half Spanish-speaking) aged 40 and over, and investigate their impact on neurocognitive status cross-sectionally and longitudinally over the course of three years. We will leverage existing longitudinal data from the UCSD HIV Neurobehavioral Research Program to select a comparison group of 100 HIV+ non-Hispanic Whites. To ensure the success of the proposed multidisciplinary approach, we have assembled a research team representing an integration of relevant disciplines, including cross-cultural neuropsychology, health disparities, medicine, public health, microbiomics, geography, and bioinformatics, and information systems. Recognizing the importance of a community-based participatory research approach in the study of health disparities, we have partnered with community clinics and stakeholders whose input has helped strengthen our approach and assure its relevance to the community. We will build on existing cross-sectional studies in Hispanics led by the PI for recruitment of participants into the proposed study, and our community partnerships will help assure that we reach the most vulnerable segments of the Hispanic community. With this multidisciplinary and community integrated approach to research, we aim to increase our understanding of the complexity that underlies mechanisms of disparities in neurocognitive outcomes among diverse groups of Hispanics aging with HIV. Such knowledge is crucial for the development of targeted, culturally relevant interventions to prevent or ameliorate HIV-associated NCI among Hispanics and reduce health disparities.